GGPP-mediated modulation of APP processing

GGPP 介导的 APP 加工调节

• 批准号: 7477637
• 负责人: YAN ZHOU
• 金额: $ 6.66万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477637
• 关键词: Aftercare; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Anabolism; Blood; Brain; C-terminal; Cardiovascular Diseases; Cholesterol; Clinical; Complex; Detergents; Development; Disease; Drug Delivery Systems; Epidemiologic Studies; Future; Generations; Genetically Engineered Mouse; Geranylgeranyl-diphosphate geranylgeranyltransferase; Health; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro; Knowledge; Mediating; Membrane; Membrane Microdomains; Metabolism; Monomeric GTP-Binding Proteins; Pathway interactions; Patients; Peptides; Play; Population; Post-Translational Protein Processing; Prevalence; Prevention; Process; Protein C; Protein Fragment; Proteins; Regulation; Reporting; Research; Role; Signal Transduction; Small Interfering RNA; Testing; Transgenic Organisms; amyloid peptide; amyloid precursor protein processing; amyloidogenesis; atorvastatin; base; clinically relevant; disorder prevention; farmer; geranylgeranyl pyrophosphate; in vivo; insight; isoprenoid; mevalonate; mouse model; novel; novel therapeutics; prevent; rho; secretase

DESCRIPTION (provided by applicant): Statins can reduce A¿ generation both in vitro and in vivo, which provides a possible explanation for their clinical benefits in Alzheimer's disease (AD) prevention. However, it has been shown that the levels of cholesterol and A¿ are not correlated in the brain of transgenic AD mouse models treated with atorvastatin or in mice genetically engineered to have low blood cholesterol levels. Therefore, the notion that statins act simply via cholesterol-lowering may need to be examined more carefully. As inhibitors of HMG-CoA reductase, statins inhibit the biosynthesis of many metabolites downstream of mevalonate, including cholesterol and isoprenoids. We have found that geranylgeranyl pyrophosphate (GGPP), an isoprenoid generated in the mevalonate biosynthetic pathway, preferentially increases the levels of amyloidogenic A¿42 through the activation of Rho/Rock signaling. We have also found that the cleavage of APP fragments by secretase is GGPP dependent. Furthermore, supplement of GGPP can fully reverse statin-mediated A¿ reduction. Based on our findings, we hypothesize that cellular GGPP may play an important role in the amyloidogenesis of AD; and through inhibiting the synthesis of GGPP, statins reduce A¿ generation. To test this hypothesis, we will first determine the relation between cellular GGPP levels and and A¿ generation in specific aim #1. We will then investigate whether the inhibition of Rho/Rock signaling is a mechanism of statin-mediated changes in APP-CTF processing and A¿ generation in specific aim #2. The information generated by the proposed studies will broaden our knowledge of the mechanisms of statins in the treatment of AD and provide more specific drug targets. Our studies will also set a start point for future research to develop novel therapeutic approaches to prevent AD based on the regulation of isoprenoids and Rho/Rock signaling. Statins, which have been shown to reduce the prevalence of Alzheimer's disease, inhibit the synthesis of both cholesterol and GGPP. We have found that GGPP alters the metabolism of APP and promote the synthesis amyloid-¿-peptide, a protein important in the development of the disease. We will be able to define the underlying mechanisms through proposed studies, thus providing new drug targets for the prevention and treatment of Alzheimer's disease.

描述（由申请人提供）：他汀类药物可以在体外和体内减少Aβ的产生，这为其预防阿尔茨海默氏病（AD）的临床益处提供了可能的解释。然而，已经表明，在用阿托伐他汀治疗的转基因 AD 小鼠模型或经过基因工程改造具有低血液胆固醇水平的小鼠的大脑中，胆固醇和 A 的水平不相关。因此，他汀类药物仅通过降低胆固醇发挥作用的观点可能需要更仔细地检验。作为 HMG-CoA 还原酶的抑制剂，他汀类药物可抑制甲羟戊酸下游许多代谢物的生物合成，包括胆固醇和类异戊二烯。我们发现香叶基香叶基焦磷酸 (GGPP) 是甲羟戊酸生物合成途径中产生的类异戊二烯，可通过激活 Rho/Rock 信号传导优先增加淀粉样蛋白 A¿42 的水平。我们还发现分泌酶对 APP 片段的切割是 GGPP 依赖性的。此外，补充 GGPP 可以完全逆转他汀类药物介导的 A¿ 减少。根据我们的发现，我们假设细胞 GGPP 可能在 AD 淀粉样蛋白生成中发挥重要作用。他汀类药物通过抑制 GGPP 的合成，减少 A¿ 的产生。为了检验这一假设，我们将首先确定特定目标#1 中细胞 GGPP 水平和 A¿ 生成之间的关系。然后，我们将研究 Rho/Rock 信号传导的抑制是否是他汀类药物介导的 APP-CTF 加工和 A¿ 生成变化的机制（具体目标 #2）。拟议研究产生的信息将拓宽我们对他汀类药物治疗 AD 机制的了解，并提供更具体的药物靶点。我们的研究还将为未来的研究奠定一个起点，以开发基于类异戊二烯和 Rho/Rock 信号传导的调节预防 AD 的新治疗方法。他汀类药物已被证明可以降低阿尔茨海默病的患病率，并抑制胆固醇和 GGPP 的合成。我们发现GGPP改变APP的代谢并促进淀粉样-β-肽的合成，淀粉样-β-肽是一种在疾病发展中重要的蛋白质。我们将能够通过拟议的研究来确定潜在的机制，从而为预防和治疗阿尔茨海默病提供新的药物靶点。